Therapeutic composition containing 1-(2-hydroxy-2-indanyl)-propylamine

ABSTRACT

This invention relates to a therapeutic composition having particularly an anoretic and lipolytic activity comprising, as active ingredient, 1-(2-hydroxy-2-indanyl)-propylamine or a therapeutically administrable salt thereof.

O United States Patent [191 [111 3,885,045 Maillard May 20, 1975 [54] THERAPEUTIC COMPOSITION 3,072,756 141363 Heubner 352330 TAINI G 3,505,4 4 4 l 70 Petersen eta 330 HYDREXY Z INDANYL) 3,657,440 4/1972 Werner 424/330 PROPYLAMINE OTHER PUBLICATIONS [75] Invent: Gemges Mallard Pans Maillard et 31., Chemical Abstracts, 67:1085788 (1967). [73] Assignee: Laboratoires Jacques Logeais,

IssylaSMOulmCaux France Primary Examiner-Stanley J. Friedman [22] Filed: July 19, 1973 Assistant ExaminerNorman A. Drezin Attorney, Agent, or FirmCooper, Dunham, Clark, [21] Appl. No.. 380,542 Griffin & Moran [30] Foreign Application Priority Data July 20, 1972 France 72.26162 ABSTRACT This invention relates to a therapeutic composition (SL having particularly an anoretic and lipolytic activity [58] Fie'ld 424/330 comprising, as active ingredient, l-(2-hydroxy-2- indanyl)-propylamine or a therapeutically administra- [56] References Cited ble Salt thereof UNITED STATES PATENTS 5/1961 Schenck et al. 424 330 6 Claims, No Drawings THERAPEUTIC COMPOSITION CONTAINING 1-(2-I-IYDROXY-2-INDANYL)-PROPYLAMINE Scheme.

1) 11 ClNH L 3) E RC1 The base is a white crystalline solid, M.p. 9899C.

This compound has been disclosed as having no particular pharmacological activity.

Applicant has now found that l-(2-hydroxy-2- indanyl)-propylamine and its therapeutically acceptable salts possess useful anoretic and lipolytic properties.

The more commonly employed therapeutically useful anoretics are phenethylamines and particularly amphetamine derivatives, which exhibit two major drawbacks:

they are strong stimulants of the central nervous system;

they produce an acceleration of the heart rhythm.

On the other hand, in view of the fact that they are active at the level of the central nervous system, the weight loss they produce is predominantly related to a decrease of appetite, without substantial influence at the level of the adipose tissues.

In contrast, l-(2-hydroxy-2-indanyl)-propylamine possesses both anoretic and lipolytic properties evidenced in rat and in the adipose tissues in vitro. Moreover, its effects on the central nervous system and the cardiovascular system are negligible. This material was found to be more sedative than stimulant and the only manifest cardiac activity is a protection against some types of experimental arrhythmias in animals. v

The pharmacological and toxicological testsreported below were conducted with l-(2-hydroxy-2-indanyl)- propylamine hydrochloride.

1. Anoretic action in rats (cf. R. CI-IAILLET and coworkers, Arch. Int. Pharmaco, 1966. 144, 451) Lots of 6 male rats weighing -160 g are placed in individual cages and are fasted during 48 hours, while being allowed to drink at will. The material is administered orally, 30 minutes prior to the test. The food, which is offered to the animals in feeding-troughs, is weighed every hour during 6 hours. For each lot of animals, the food intake is calculated per 100 g of body weight and is compared every hour with the food intake of a reference lot.

Results:

30 mg/kg 30% decrease of food intake period of time: 1 hour 60 mg/kg 25-30% decrease of food intake period of time: 6 hours Throughout the testing time, the animals retain a behavior and an activity identical with those of the controls.

2. Lipolytic action In vivo:

The test material is injected subcutaneously to male and female rats weighing -180 g (5-15 animals per dosage level). Blood samples are taken after decapitation, 60 minutes after the injection. The fatty acids released by lipolysis are assayed in the heparinized plasma, according to the conventional technique of DUNCOMBE.

Dosage Free fatty acid level (micromoles/ml) with respect to the treated control control animals animals animals 10 mg/kg 284 i 55 325 i 27 12.6 30 mg/kg 262 i 30.7 192 i 14 36 100 mg/kg 354 i 21.7 232 i 24 54 The fatty acids released are assayed on 0.5 ml by the technique according of DUNCOMBE.

Compound Concentration Free fatty acids added (micromoles/g of tissue/hour) 2.63 noradrenalin l" M 9.43 test material IOM 2.03 test material l0 M 3.97 test material IOM 4.26 test material l0' M 4.70

Thus, the test material possesses a substantial lipolytic activity from a level of l0 M.

3. Actions on the central nervous system Spontaneous activity of mice grouped in lots of 12, measured between 25 and 35 minutes after administration of the test material.

Oral administration variation with respect to the controls 25 mg/kg 6.7%

50 mg/kg 29 I00 mg/kg 44 Intraperitoneal administration variation with respect to the controls 25 mg/kg 50 mg/kg 46 I00 mg/kg 75 Potentiation of barbiturate induced sleep in micegiven a non-hypnotic dose of nembutal mg/kg I.P.): substantially none at 50 mg/kg I.P.

Analgesia (mice): DAMOUR and SMITH tests (J. Pharmacol. Exp. Ther., 1941, 72, 74) and KOSTER test (B. KOSTER and M. ANDERSON, Fed. Proc., 1959, I8, 412): no action at 60 mg/kg LP. or per 0s.

4. Cardiovascular actions Protection against extra-systoles and ventricular tachycardia induced in rat by injection of aconitin nitrate: at 30 mg/kg, the test material protects almost completely the test animals against said symptoms.

Protection against heart fibrillation induced in mice by immersion in a chloroform-saturated atmosphere:

none.

Electro-systolic entrainment in rabbits: a double electric probe is introduced in the vena cava at the level of the right auricle and the electric entrainment of the heart is set at a frequency 5% above normal. By gradually increasing the frequency, the maximum value which may be followed by the heart is tested at 5 minute intervals and checked with an oscilloscope. At a a Tablets containing l-(2-hydroxy-2-indanyl)-propylamine (base) l-(2-hydroxy-2-indanyl)-propylamine (base) Starch b Capsules containing l-(2-hydroxy-Z-ifldanyD-propylamine (base) Il-(2-hydroxy-2-indanyl)-propylamine (base) 2 actose dosage of 60 mg/kg by the duodenal route, the test material decreases by a factor of 50% the maximum frequency followed, with respect to the normal value (decrease of cardiac excitability).

Recording of blood pressure, of the electrocardiogram, of the frequency and of the heart rate of flow and of the femoral rate of flow in nembutalanesthetized dog; no change of said parameters is found to occur up to a dosage of 5 mg/kg I.V. of the test material. From a dosage of 5 mg/kg I.V., a slight decrease of the carotid blood pressure is noted.

5. Absence of choleretic (in rats), diuretic (in rats) and antihistaminic (in guinea-pigs) actions Chronic toxicity:

Male rats weighing -100 g are given the test material in admixture with food, at a rate of 100, 30 and 10 mg of test material per day.

Ten rats were used at each dosage level. Mice were treated in a similar manner (10 animals per dosage level).

Samples of blood and organs were taken after 4, 8 and 12 weeks and the results obtained were compared with those obtained with reference animals. The glycemia, uremia, cholesterolemia, calcemia, phosphoremia, proteinemia and albuminemia levels and the histologic examinations of the kidneys, the suprarenal glands, the livers, the pancreas, the spleens, the hearts, the lungs, the thymus glands and the testicles are substantially normal in all the treated animals.

In contrast, the free fatty acid level in the blood plasma is strongly increased in the treated animals, even at 10 mg/kg. The food intake of the treated animals is substantially less than that of the controls.

In addition, rats given 5 times a week, during 6 weeks, 60 mg/kg of test material suspended in carboxymethylcellulose and administered by esophageal tube have shown normal biological constants and organs.

The clinical tests carried out confirmed the results of the pharmacologic experiments.

The test material was administered to patients in the form of tablets containing 50 or mg active material, at a rate of 100-500 mg/day. After 2-6 days of treatment with mg/day, all subjects displayed a distaste for food and a weight loss of l-3 kg. No phenomenon of intolerance was noted up to dosages of 500 mg/day.

. The test material has a definite therapeutic usefulness in the treatment of obesity without any fear of troublesome nervous or cardiovascular manifestations.

The therapeutic composition according to the invention may be advantageously administered orally, particularly in the form of capsules or tablets containing 20-200 mg active ingredient.

Examples of suitable formulation are given below 80 mg 200 mg -Continued Magnesium stearate 2 mg 0 Capsules containing l-(2-hydroxy-2-indanyl)-propylamine hydrochloride l-( 2-hydroxy-2-indanyl )-propylamine hydrochloride 120 mg Magnesium stearate 2 mg Polyvinyl pyrrolidone 3 mg Talc mg Having now described my invention, what I claim as administered as a composition containing from to new and desire to secure by Letter Patent is: 200 mg f the compound 1. A method for the treatment of obesity which com- 10 prises administering to an obese host a pharmaceutical composition containing an anoretically effective quan- 4. A method as in claim 3 wherein the composition is in the form of a capsule.

tity of a compound selected from the group consisting 5. A method as in claim 3 wherein the composition of 1-( 2-hydroxy-2-indanyl)-propylamine and the phari i th form of a tablet. maceutically acceptable salts thereof. 15 h d 2. A method as in claim 1 wherein the compound is A method a m clam 1 whersm t e compoun administered orally. 1-(2-hydroxy-2-mdanyl)-propylamine. 3. A method as in claim 2 wherein the compound is 

1. A METHOD FOR THE TREATMENT OFOBESITY WHICH COMPRISES ADMINISTERING TO AN OBESE HOST A PHARMACEUTICAL COMPOSITION CONTAINING AN ANORETICALLY EFFECTIVE QUANTITY OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-(2-HYDROXY-2INDANYL)-PROPYLAMINE AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.
 2. A method as in claim 1 wherein the compound is administered orally.
 3. A method as in claim 2 wherein the compound is administered as a composition containing from 20 to 200 mg of the compound.
 4. A method as in claim 3 wherein the composition is in the form of a capsule.
 5. A method as in claim 3 wherein the composition is in the form of a tablet.
 6. A method as in claim 1 wherein the compound is 1-(2-hydroxy-2-indanyl)-propylamine. 